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Aims: The aim of this study is to assess baseline characteristics of drusen preceding the development of intraretinal hyper-reflective foci (IHRF) in eyes with intermediate age-related macular degeneration (AMD)., Methods: In this retrospective case-control study, longitudinal optical coherence tomography (OCT) volume data from eyes with intermediate AMD in a retina clinic population were screened. All drusen that developed overlying IHRF were marked. A random number generator was used to select for further grading three drusen that did not develop IHRF., Results: Ninety eyes (from 72 patients), including 140 drusen with overlying IHRF and 270 IHRF- drusen, were analysed. Greater drusen height, basal drusen width and overlying ellipsoid zone (EZ) and external limiting membrane disruption were associated with a significantly greater risk for IHRF development (p≤0.001). Regression analysis revealed EZ disruption increased these odds by 4.1 (p≤0.001). Each 10-µm increase in drusen height and width increased the odds by 34% (p≤0.001) and 3% (p: 0.005), respectively. Each 100-µm increase in distance from the fovea decreased the odds by 10% (p: 0.013)., Conclusions: The presence of overlying EZ disruption and a greater drusen height substantially increased the risk for IHRF development, whereas drusen further from the fovea indicated reduced risk. Given the importance of IHRF as a biomarker for AMD progression, these findings may be of value in defining patient populations for future early intervention trials., Competing Interests: Competing interests: SriniVas R. Sadda receives support from 4DMT, Alexion, Allergan, Alnylam Pharmaceuticals, Amgen Inc Apellis Pharmaceuticals, Astellas, Bayer Healthcare Pharmaceuticals, Carl Zeiss Meditec, Catalyst Pharmaceuticals, Centervue, GENENTECH, Gyroscope Therapeutics, Heidelberg Engineering, Iveric Bio, Janssen Pharmaceuticals, Merck & Co., Nanoscope, Nidek Incorporated, Novartis Pharma AG, Optos, Oxurion/ Thrombogenics, Pfizer, Regeneron Pharmaceuticals, Samsung Bioepis, Topcon Medical Systems, Vertex Pharmaceuticals Incorporated. David Sarraf receives support from Amgen, Bayer, Endogena Therapeutics, Genentech, Iveric Bio, Novartis and Optovue/Visionix and receives research grants from Amgen, Boehringer, Genentech, Heidelberg, Optovue/Visionix, Regeneron, and Topcon. Charles C. Wykoff receives support from 4DMT, AbbVie, Adverum, Aerie, AGTC, Alcon, Alimera, Allergan, Allgenesis, Alnylam, Annexon, Apellis, Arrowhead, Bausch + Lomb, Bayer, Bionic Vision, Boehringer Ingelheim, Chengdu Kanghong, Cholgene, Clearside, Curacle, EyePoint, Foresite, Frontera, Genentech, Gyroscope, IACTA, IVERIC Bio, Janssen, Kato, Kiora, Kodiak, Kriya, Merck, Nanoscope, NGM, Notal Vision, Novartis, OccuRx, Ocular Therapeutix, Ocuterra, OliX, ONL, Opthea, Palatin, PerceiveBio, Perfuse, PolyPhotonix, Ray, RecensMedical, Regeneron, RegenXBio, Resonance, Roche, SciNeuro, Stealth, Surrozen, THEA, TissueGen, Valo, Verana, Vitranu. Grants from ongoing relationships as a Principal Investigator with: 4DMT, Adverum, Aerie, AffaMed, Aldeyra, Alexion, Alimera, Alkahest, Allergan, Allgenesis, Amgen, Annexin, Annexon, Apellis, Asclepix, Bayer, Boehringer Ingelheim, Chengdu Kanghong, Clearside, Curacle, EyePoint, Gemini, Genentech, Graybug Vision, Gyroscope, IONIS, iRENIX, IVERIC bio, Kodiak, LMRI, Nanoscope, Neurotech, NGM, Novartis, Ocular Therapeutix, Ocuphire, OcuTerra, Opthea, Oxurion, Oxular, Oyster Point, Perceive Biotherapeutics, RecensMedical, Regeneron, RegenXBio, Roche, SamChunDang Pharm, Sandoz, Taiwan Liposome Company, UNITY, Verily, Xbrane. Stock Options (not owner) from ongoing relationships as a Consultant from Private Companies: ONL, PolyPhotonix, RecensMedical, TissueGen, Visgenx, Vitranu. Giulia Corradetti receives support from Nidek. Muneeswar Gupta Nittala receives support from Eyenuk., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To analyse the morphological characteristics of eyes with neovascular age-related macular degeneration (AMD) with good long-term visual acuity after anti-VEGF (vascular endothelial growth factor) therapy., Methods: Retrospective, observational study of 175 patients with neovascular AMD with >5 years of follow-up after initiating anti-VEGF therapy. Spectral-domain optical coherence tomography images were assessed for thickness of pigment epithelial detachment (PED), subretinal hyper-reflective material (SHRM), subretinal fluid and subfoveal choroidal, as well as the integrity of the outer retinal bands., Results: The final analysis cohort included 203 eyes (175 patients) followed for a mean of 7.84±1.70 years (range: 5-11). The maximum PED thickness in the foveal central subfield (FCS) was significantly lower (p<0.001) in the poor vision group (13.11 μm) compared with the intermediate (86.25 μm) or good (97.92 μm) vision groups, respectively. In contrast, the maximum thickness of SHRM in the FCS was significantly thicker (p<0.001) in eyes with poor vision (149.46 μm) compared with eyes with intermediate vision (64.37 μm) which in turn were significantly thicker (p<0.001) than eyes with good vision (9.35 μm). The good vision group also had better continuity of all outer retinal bands (external limiting membrane, ellipsoid zone, and retinal pigment epithelium) compared with the other two groups (all p<0.001)., Conclusion: A thicker PED and thinner SHRM were correlated with better vision in eyes with neovascular AMD following long-term anti-VEGF therapy. If replicated in future prospective studies, these findings may have implications for design of optimal anatomic endpoints for neovascular AMD treatment., Competing Interests: Competing interests: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. CW reported receiving grants, personal fees or nonfinancial support from Adverum, Aerie Pharmaceuticals, Aldeyra, Alimera Sciences, Allergan, Apellis, Arctic Vision, Arrowhead, Bausch + Lomb, Bayer, Bionic Vision Technologies, Boehringer Ingelheim, Chengdu Kanghong Biotechnologies (KHB), Clearside Biomedical, EyePoint, Gemini Therapeutics, Genentech, Graybug Vision, Gyroscope, IONIS Pharmaceutical, IVERIC Bio, Kato DSRC, Kodiak Sciences, LMRI, Neurotech Pharmaceuticals, NGM Biopharmaceuticals, Novartis, OccuRx, Ocular Therapeutix, ONL Therapeutics, Opthea, Outlook Therapeutics, Oxurion (formerly Thrombogenics), Palatin, Pentavision, PolyPhotonix, RecensMedical, Regeneron, RegenXBio, Roche, SAI MedPartners, SamChunDang Pharm., Santen, Senju, Taiwan Liposome Company, Takeda, Thea Open Innovation, Verana Health, Visgenx, Xbrane BioPharma. DS reported receiving grants, personal fees, or nonfinancial support from Amgen, Genentech, Heidelberg, Optovue, Regeneron, Topcon, Bayer, Iveric Bio, Novartis. SS reported receiving grants, personal fees, or nonfinancial support from Carl Zeiss Meditec, Nidek, Topcon, Heidelberg, Optos, Centervue, Amgen, Allergan, Genentech/Roche, Oxurion, Novartis, Regeneron, Bayer, 4DMT, Merck, Apellis, Astellas., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: This study investigates the association of intraocular cytokine expression and ultrawide-field fluorescein angiography (UWFA) quantitative imaging biomarkers and their association with angiographical feature response after antivascular endothelial growth factor (VEGF) therapy in diabetic macular oedema (DME)., Methods: The IMAGINE DME study is a post hoc imaging biomarker and intraocular cytokine assessment from the DAVE study, a prospective DME clinical trial that included aqueous humour sampling and UWFA imaging. Fifty-four cytokines associated with inflammation and angiogenesis were evaluated through multiplex arrays. UWFA parameters were assessed using an automated feature analysis platform to determine ischaemic and leakage indices and microaneurysm (MA) count. Eyes were classified into UWFA responder or non-responder groups based on longitudinal quantitative UWFA parameter improvement. Cytokine expression was correlated with UWFA metrics and evaluated in the context of therapeutic response., Results: Twenty-one eyes were included with a mean age of 55±10 years. Increased panretinal leakage index correlated with VEGF (r=0.70, p=0.0005), angiopoietin-like 4 (r=0.77, p=4.6E-5) and interleukin (IL)-6 (r=0.64, p=0.002). Panretinal ischaemic index was associated with tissue inhibitor of metalloproteinases 1 (TIMP-1, r=0.49, p=0.03) and peripheral ischaemia correlated with VEGF (r=0.45, p=0.05). MA count correlated with increased monocyte chemotactic protein-4 (MCP-4, r=0.60, p=0.004) and platelet and endothelial cell adhesion molecule 1 (PECAM-1, r=0.58, p=0.005). Longitudinal MA reduction was associated with decreased baseline VEGF and urokinase receptor (uPAR) (p<0.05). High baseline VEGF and IL-6 were associated with dramatic reduction in macular leakage (p<0.05)., Conclusions: Baseline and longitudinal quantitative UWFA imaging parameters correlated with multiple aqueous humour cytokine concentrations, including VEGF and IL-6. Further research is needed to assess the possible implications of using these findings for evaluating treatment response., Competing Interests: Competing interests: JRA, SA, LL, HJY, MH, JR: none; CCW, Adverum (research funding (F)), Alimera Sciences (consultant (C)) Allergan (C, F), Allegro (C), Apellis (C, F), Alynylam (C), Bayer (C), Clearside (C, F), DORC (C), EyePoint (C, F), Genentech/Roche (C, F), Kodiak (C), Neurotech (F), Notal Vision (C), ONL Therapeutics (C), Novartis (C, F), Polyphontonix (C), Regeneron (C, F, S), Regenxbio (C, F), Samsung (F), Santen (C, F); SKS: Regeneron (F), Allergan (F), Gilead (F), Bausch and Lomb (C), Santen (C), Leica (patent (P)); DMB, Adverum (F) Allergan (C, F), Apellis (F), Bayer (C), Biotime (C), Clearside (F), Chengdu Kanghong Biotechnology (C), Gemini (C), Genentech/Roche (C, F), Heidelberg (C), Novartis (C, F), OHR (C), Opthea (F), Optos (C), Zeiss (C), Regeneron (C, F), Regenxbio (C, F), Samsung (F), Santen (C), Senju (C); JPE: Aerpio (C, F), Alcon (C, F), Thrombogenics/Oxurion (C, F), Regeneron (C, F), Genetech (C, F), Novartis (C,F), Allergan (C, F), Roche (C), Leica (C, P), Zeiss (C), Santen (C)., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: To quantify retinal vascular bed area (RVBA) in square millimetres on stereographically projected ultra-wide field (UWF) fluorescein angiography (FA) in eyes with diabetic retinopathy (DR)., Methods: A prospective, observational study. Baseline Optos 200Tx UWF FA images of 80 eyes with DR from the DAVE (NCT01552408) and RECOVERY (NCT02863354) studies were stereographically projected at the Doheny Image Reading Center to adjust for peripheral distortion. The early-phase FA frame was used to extract the retinal vasculature as a mask for calculating RVBA. The pixels of the retinal vasculature were automatically computed in square millimetres using manufacturer-provided software., Results: Eighteen of 80 diabetic eyes were excluded because image quality and contrast were insufficient for automatic extraction of the retinal vasculature from the background fluorescence. The remaining 62 eyes were included in the final analysis. In comparison with age-matched and sex-matched normal controls, eyes with DR had a higher global RVBA for the entire retina (p<0.001), and RVBA correlated with DR severity (p<0.001), with a higher RVBA in eyes with proliferative DR (66.1±16.2 mm 2 ) than in those with non-proliferative DR (56.2±16.6 mm 2 ) or in normal controls (37.2±9.9 mm 2 ). This tendency was also present in the posterior retina and mid-periphery but absent in the far-periphery. RVBA did not correlate with retinal ischaemia (p>0.05)., Conclusions: Eyes with DR harboured a larger global RVBA for the entire retina than normal controls, and RVBA appeared to indicate DR severity. However, this biomarker was not observed to be a good indicator of retinal ischaemia., Competing Interests: Competing interests: SS reported receiving grants, personal fees or non-financial support from Carl Zeiss Meditec, Optos, Allergan, Genentech, Alcon, Novartis, Roche, Regeneron, Bayer, Thrombogenics, StemCells Inc and Avalanche. MSI reported receiving grants, personal fees or non-financial support from Thrombogenics, Omeros, Boehringer Ingelheim and Genentech., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background/aims: Quantifying microaneurysms (MAs) turnover may be an objective measure for therapeutic response in diabetic retinopathy. This study assesses changes in MA counts on ultra-widefield fluorescein angiography (UWFA) in subjects undergoing treatment with intravitreal aflibercept injection (IAI) for proliferative diabetic retinopathy (PDR) in the Intravit re al Afliber c ept for Retinal N o n-Perfusion in Proliferati v e Diab e tic R etinopath y (RECOVERY) study using an automated MA detection platform., Methods: RECOVERY is a prospective study that enrolled 40 subjects with PDR randomised 1:1 to receive 2 mg IAI every 4 weeks(q4wk) or every 12 weeks (q12wk). UWFA images were obtained at baseline, 6 months and 1 year. Images were analysed using an automated segmentation platform to detect and quantify MAs. Zones 1, 2 and 3 correspond to the macula, mid-periphery and far-periphery, respectively., Results: The q4wk cohort demonstrated a significant decline in MAs in all zones and panretinally at baseline versus month 6, baseline versus year 1, and month 6 versus year 1 (-20.0% to -61.8%; all p<0.001). In the q12wk cohort, baseline versus month 6 showed a significant decline panretinally (mean: -34.2%; p<0.001) and in zone 3 (mean -44.18%; p<0.001). Addiitonally, baseline to year 1 in the q12wk group demonstrated significant decline panretinally (mean: -47.7%; p<0.001) and in zone 3 (mean: -59.8%; p<0.001). All zones demonstrated significantly decline from month 6 to year 1 in the q12wk group., Conclusion: Therapy with IAI demonstrates significantly reduced panretinal MA counts in PDR at 1 year in both treatment groups. The use of automated platforms to detect and quantify MAs may provide a novel imaging marker for evaluating disease activity and therapeutic impact., Trial Registration Number: NCT02863354., Competing Interests: Competing interests: AB, research support—Genentech, Allergan; consulting—Genentech; CCW, research support—Adverum, Allergan, Apellis, Clearside, EyePoint, Genentech/Roch, Neurotech, Novartis, Opthea, Regeneron, Regenxbio, Samsung, Santen; consulting—Adverum, Alimera Sciences, Allegro, Allergan, Apellis, Bayer, Clearside, DORC, EyePoint, Genentech/Roche, Kodiak, Notal Vision, Novartis, ONL Therapeutics, PolyPhotonix, RecensMedical, Regeneron, Regenxbio, Santen, Takeda; SS, research support—Regeneron, Allergan, Gilead; consulting: Bausch and Lomb, Santen; patent—Leica; SVRS, research support—Carl Zeiss Meditec, consulting—Optos, CenterVue, Heidelberg Engineering, Roche/Genentech, Novartis, Allergan, Amgen, Bayer; research instruments—Carl Zeiss Meditec, Nidek, Topcon; JPE, research support—Aerpio, Alcon, Thrombogenics, Regeneron, Genentech, Novartis; consulting—Aerpio, Alcon, Allegro, Allergan, Genentech/Roche, Novartis, Thrombogenics, Leica, Zeiss, Regeneron, Santen; patent—Leica; MI, consultant: Boehringer Ingelheim, Thrombogenics, Quark, Omeros, Allergan, Amgen, Astellas, Alimera; research support—Novartis, Genentech, Clearside, Biogen. KET, HJY, MN MH, JR, no competing interests., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background/aims: To evaluate the long-term effects of treat-and-extend dosing of ranibizumab with and without navigated focal laser for diabetic macular oedema (DME)., Methods: This is a multicentre, randomised clinical trial where 150 eyes were randomised into three cohorts; Monthly (n=30), TReat and EXtend without macular laser photocoagulation (TREX; n=60), and treat and extend with angiography-GuIded macular LAser photocoagulation (GILA; n=60). During the first 2 years, eyes either received ranibizumab 0.3 mg every 4 weeks or underwent treat-and-extend ranibizumab with or without angiography-guided laser therapy. In the third year, all eyes were treated as needed with ranibizumab for >5 letters vision loss or if the central retinal thickness (CRT) was >325 µm, and all eyes were eligible to receive focal laser., Results: 109 eyes (73%) completed the 3-year end-point. At week 156, mean best-corrected visual acuity (BCVA) and CRT improved by 6.9, 9.7, 9.5 letters (p=0.60) and 129, 138, 165 µm (p=0.39), in the Monthly, TREX and GILA cohorts, respectively. These improvements were reached prior to week 104 and no significant changes occurred from week 104 to week 156 (BCVA: p=0.34; CRT: p=0.36). The mean number of injections in the third year was 3.0, 3.1, and 2.4 in the Monthly, TREX and GILA cohorts, respectively (p=0.56). 86 eyes (79%) required at least one ranibizumab injection in the third year., Conclusion: The improvements achieved after 2 years of treat-and-extend ranibizumab for DME were maintained in the third year with a mean of 3 intravitreal injections., Trial Registration Number: FDA IND 119146, NCT01934556., Competing Interests: Competing interests: JP: Received research grant funding for TREX-DME from Genentech. Has also received research grant funding from Genentech, Regeneron and the Diabetic Retinopathy Clinical Research Network. CCW: Received personal fees from Acucela, Aerpio, Alimera, Allegro, Allergan, Apellis, Bayer, Chengdu Kanghong, Clearside Biomedical, DORC, Eyepoint, Genentech/Roche, Iveric Bio, Kodiak, Novartis, ONL Therapeutics, Outlook Therapeutics, Oxurion, PolyPhotonics, Recens Medical, Regeneron, Regenxbio, Santen and Takeda. Received research grant funding from Adverum, Aerie Pharmaceuticals, Aerpio, Allergan, Apellis, Chengdu Kanghong, Clearside Biomedical, Gemini Therapeutics, Genentech/Roche, Graybug Vision, IONIS Pharmaceuticals, Iveric Bio, Kodiak, Neurotech, Novartis, Ophthea, Outlook Therapeutics, Recens Medical, Regeneron, Regenxbio, Samsung, Santen and Xbrane Biopharma. WLC: Received personal fees from Regeneron, Genentech, Diabetic Retinopathy Clinical Research Network, Thrombogenics and Ophthea. BB: Received personal fees from Genentech, Emory University, Bayer, Medimmune and individual litigants. DSB: Received personal fees from Alcon, Allegro, Allergan, Bayer, Chengdu Kanghong and Regeneron. DB: Received personal fees from Novartis, Regeneron, Bayer, Genentech/Roche, Adverum, Kodiak, Senju, Chengdu Kanghong, Boehringer Ingelheim, Allegro, Apellis, Gemini, Regenxbio, Stealth, Santen, Heidelberg, Optos, Navilas, Ocular Therapeutics, iRenix and Lineage Cell. Received research grant funding from Novartis, Regeneron, Bayer, Genentech/Roche, Adverum, Kodiak, Senju, Chengdu Kanghong, Boehringer Ingelheim, Allegro, Apellis, Gemini, Regenxbio, Stealth, Santen, Heidelberg, Optos, Navilas, NEI, NGM, Ionis, Outlook Therapeutics, Xbrane Biopharma and Graybug Vision., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: To evaluate changes in the ischaemic index (ISI) after targeted retinal photocoagulation (TRP) and to investigate the correlation between these changes and macular oedema (ME)., Method: Twenty-four eyes of 24 patients with retinal vein occlusion (RVO) with recurrent ME were included. Ultra-widefield fluorescein angiography (UWFFA; Optos 200Tx) was obtained at baseline and every 4 months. The regions of retinal non-perfusion and the total gradable retina were manually segmented on UWFFA images for calculating the global ISI. ISI was also computed for specific regions defined by a standardised grid: perimacular area (PMA), near-peripheral area (NPA), mid-peripheral area (MPA) and far-peripheral area (FPA). Global and regional ISIs and change in ISI over time were correlated with central macular thickness (CMT)., Results: The ISIs of entire retina, PMA, NPA, MPA and FPA at baseline were 30.5%±23.3, 17.7%±20.6, 21.9%±19.0, 33.0%±27.9 and 48.0%±32.9, respectively. The ISIs at final follow-up were 23.5%±19.9, 15.7%±22.2, 16.5%±16.7, 24.7%±24.7 and 24.7%±24.7, respectively. A significant correlation was found between CMT and global ISI during follow-up (r=0.22, p=0.03). Among the different retinal zones, PMA showed a correlation with CMT (r=0.27, p=0.007). The change in ISI for the total retina (Δtotal), PMA (ΔPMA) and NPA (ΔNPA) retinal regions was positively correlated with the change in CMT (ΔCMT) (r=0.45, 0.42 and 0.50, respectively, p=0.006, 0.009 and 0.002, respectively)., Conclusion: The severity of ME was correlated with the ISIs of the entire retina and the PMA. The reduction in ME was correlated with the reduction in ISI of the entire retina as well as the ISIs for the NPA and PMA following TRP. The role of TRP, particularly to these regions (NPA, PMA), warrants further investigation in recalcitrant RVO-associated ME., Competing Interests: Competing interests: SRS is a consultant for and receives research support from Optos and Carl Zeiss Meditec, and serves as a consultant for Centervue, and has access to research instruments provided by Heidelberg Engineering, Topcon Medical Systems, Optos, Carl Zeiss Meditec, Nidek, and Centervue., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Aim: To determine the efficacy of 2.0 mg aflibercept in the management of patients with recalcitrant exudative age-related macular degeneration (AMD)., Methods: In this prospective, open-label, single-arm clinical trial, patients were seen monthly and given mandatory 2.0 mg aflibercept at baseline, months 1, 2 and 4. Pro re nata (PRN) retreatment at months 3 and 5 was performed upon evidence of disease on spectral domain-optical coherence tomography (SD-OCT). End point at month 6: mean change in Early Treatment Diabetic Retinopathy Study best corrected visual acuity (ETDRS BCVA) and central subfield thickness (CST), mean number of aflibercept injections, percentage of PRN injections required, patients with no fluid on SD-OCT and patients losing >15 letters., Results: At baseline, 46 patients with a mean of 42 prior antivascular endothelial growth factor-A (anti-VEGF) intravitreal treatments had a mean of 74.2 letters (Snellen equivalent 20/32) and mean CST of 347 µm. ETDRS letters remained stable throughout the trial; at month 6, mean BCVA change was +0.2 letters (range -10 to +13, p=0.71). Anatomically, mean CST improved significantly from baseline at each study visit including -23.6 µm at month 1 and -27.3 µm at month 6 (p=0.018). Seventy-one of 90 (79%) possible PRN injections were required and a mean of 5.6 aflibercept injections out of the maximum six were administered. Ten of 45 (22%) patients had no retinal fluid on SD-OCT at month 6. No patient lost >15 letters., Conclusions: Aflibercept 2.0 mg treatment maintained mean visual acuity improvements previously achieved with high-dose 2.0-mg ranibizumab injections in recalcitrant wet AMD patients. Aflibercept 2.0 mg treatment led to significant anatomic improvement and was required monthly in most patients., Clinical Trials Registration: FDA IND#12462. NCT 01543568., Trial Details: IND 12462, NCT 01543568 http://clinicaltrials.gov/show/NCT01543568., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)